Association of peripheral BDNF level with cognition, attention and behavior in preschool children

Brain-derived neurotrophic factor (BDNF) has been reported to affect development, cognition, attention and behavior. However, few studies have investigated preschool children with regard to these areas.

RESEARCH ARTICLE

Association of peripheral BDNF level

with cognition, attention and behavior

in preschool children

Abstract

Background: Brain‑derived neurotrophic factor (BDNF) has been reported to affect development, cognition, atten‑

tion and behavior However, few studies have investigated preschool children with regard to these areas We evalu‑ ated the relationship between cognition, attention and peripheral blood concentration of BDNF in preschool children

Methods: Twenty‑eight children (mean age: 6.16 ± 0.60 years) were recruited For all subjects, serum and plasma

BDNF levels were assessed; intelligence was assessed using the Korean standardisation of the Wechsler Intelligence Scale for Children (KEDI‑WISC); attention was assessed using the computerised continuous performance test (CCPT), the children’s color trails test (CCTT), the Stroop color‑word test for preschool children, and the attention‑deficit/

hyperactivity disorder rating scale (K‑ARS); and finally emotional and behavioral problems were assessed using the child behavior checklist (K‑CBCL) We confirmed the previously reported correlations between the various psychomet‑ ric properties assessed and serum and plasma levels of BDNF in our sample

Results: Serum BDNF levels were negatively correlated with both KEDI‑WISC full scale IQ (FSIQ, r = −0.39, p = 0.04)

and verbal IQ (VIQ, r = −0.05, p = 0.01), but not with the performance IQ (PIQ, r = −0.12, p = 0.56) There were no significant relationships between plasma BDNF level and VIQ, PIQ or FSIQ No correlations were found between either serum or plasma level of BDNF and any of the attentional measures (CCPT, ARS, CCTT or Stroop color word test) The CBCL total behavioral problem and attention problem sections were positively correlated with plasma BDNF level (r = 0.41, p = 0.03), (r = 0.44, p = 0.02), however, no relationship was found between the serum BDNF and any of the composite CBCL measures

Conclusions: Our results suggest that high peripheral BDNF may be negatively correlated with intelligence, behav‑

ioral problems and clinical symptoms of neuro‑developmental disorders such as intellectual disability in preschool children A high peripheral BDNF concentration may, if these findings are further replicated, prove to be a useful

biomarker for such issues in preschool children

Keywords: BDNF, Brain‑derived neurotrophic factor, Cognition, ADHD, Neurodevelopment

© 2016 Yeom et al This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/ publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Background

Brain-derived neurotrophic factor (BDNF) is a member

of the neurotrophin family, which is expressed in human

and other mammalian brains [1] BDNF is associated

with synaptic plasticity, synaptic connectivity formation

and neuronal survival [2–4] It also serves an important role during brain development [3] through the regula-tion of neural circuit development by selective embry-onic neural stem cell survival and differentiation, axonal growth and guidance, synapse formation and maturation, and the refinement of developing circuits [4]

BDNF plays an important role in learning and memory [5–7] Several reports relate BDNF levels to task perfor-mance in cognitive assessment of the rat [8–10] Admin-istration of BDNF enhances rat performance in the

Open Access

*Correspondence: dresme@hanmail.net

5 Department of Psychiatry, Eulji University School of Medicine, Eulji

General Hospital, 68 Hangeulbiseok‑Ro, Nowon‑Gu, Seoul 139‑711, South

Korea

Full list of author information is available at the end of the article

Morris water maze (MWM) [8], while injection of BDNF

antibodies into their lateral ventricles is correlated with

poorer MWM performance [9] However, Cunha et  al

[10] have suggested that chronic BDNF over-expression

in young adult transgenic mice (9–14 week) can induce

learning deficits and short-term memory impairment on

both spatial and instrumental learning tasks

A number of reports suggest a relationship between

BDNF and the functioning of certain brain areas involved

in attention and cognition [11–15] The highest levels of

CNS BDNF are found in the hippocampus, frontal

cor-tex, and amygdale [11, 12] Both endogenous BDNF and

intra-hippocampal BDNF infusion induce hippocampal

long-term potentiation, which is critical to the physiology

of long-term memory formation [13, 14] BDNF plays an

important role in the working memory of the prefrontal

cortex [15]

Currently, most research on the interrelationships

between mood, psychosis, cognition, attention and

peripheral BDNF concentration has been conducted

with adults [16–21] Relatively little research on the

asso-ciations among attention, cognition, development and

peripheral BDNF levels have been conducted with

chil-dren [22–26]

We evaluated the relationships among cognition,

atten-tion and peripheral blood BDNF concentraatten-tions in

chil-dren CNS BDNF crosses the blood-brain-barrier into

the peripheral blood [27] Some reports suggest that

serum and cortical BDNF levels are positively correlated

and that plasma BDNF levels directly reflect brain tissue

levels [28, 29]

In the present study, we have assessed serum and

plasma BDNF levels, preschool child IQ, inattention,

hyperactivity, internalized/externalized problems,

behav-ioral problems and depression in preschool children (age

range 5–7 years)

Methods

Participants

Twenty-eight preschool children [13 boys, 15 girls, mean

age: 6.16 ± 0.60 years (age range 5–7 years)] who lived in

Ulsan metropolitan city in Korea were recruited for this

study by advertisements in the Ulsan University

Hospi-tal This study was approved by the Institutional Review

Board of the Ulsan University Hospital In accordance

with the Declaration of Helsinki, both the subjects and

their parents were advised the procedure Parents of the

subject were required to provide written informed

con-sent prior to participation in the study The demographic

variables of the participants were composed of

mater-nal age at pregnancy, birth weight, patermater-nal education,

maternal education, income, and secondhand smoke

exposure

Psychometric properties

To test intelligence, we administered the Korean Edu-cational Development Institute’s Wechsler Intelligence Scale for Children (WISC) The average KEDI-WISC is 100 ± 15 [30]

Sustained attention, vigilance and distractibility were assessed by the computerized continuous performance test (CCPT) The Korean version of the CCPT is a diag-nostic tool of attention deficit-hyperactivity disorder and has acquired validity and reliability [31] CCPT comprises

an auditory and visual test that records omission error, commission error, response time and standard deviations

of response time If a T-score is more than 65 in any of these variables, ADHD is suspicious [32]

The children’s color trails test (CCTT) is the children’s version of the color trails test The CCTT assesses fron-tal lobe function, including visual-motor coordination, attention, and cognitive flexibility [33] The Korean ver-sion was standardized by Koo and Shin [34] This test scores the total time to finish (CCTT 1 and CCTT 2) and the difference interference index (total time to fin-ish CCTT 1- total time to finfin-ish CCTT 2) [34] The mean T-score of the CCTT is 50  ±  10 [35] Higher T-scores indicate better performance on the test [35]

The Stroop color-word test assesses cognitive inhibi-tion and the ability to ignore the interference from irrel-evant stimuli [36] The Korean version of the Stroop color-word test has been standardized [37] The average T-score of the Stroop color word test is 50 ± 10 [37] The Korean parent-report version of the child behavior checklist (CBCL) was used to assess child emotional and behavioral problems This version of the CBCL [38, 39] is

a 121-item questionnaire measure which is widely used

in Korea Each item is scored from 0 (absent) to 2 (very often present), and composite scores for each subscale are then converted to give T-scores with a mean of 50 and

SD of 10 [38] Five subscale scores were used to profile results in the present study, namely internalizing prob-lems; externalizing probprob-lems; total behavior probprob-lems; anxiety/depression and attention problems The exter-nalizing problems of the K-CBCL comprise attention problems and aggressive and delinquent behavior The internalizing problems consist of withdrawal; depressed behavior; and somatic complaints [40] For diagnosis of ADHD, the positive predictive value and specificity of the attention problem section is significant when the child achieves a T-score ≥60, and when the total problem sec-tion yields a T-score ≥63 [40]

ADHD screening and symptom severity was assessed

by the standardized Korean version of attention deficit hyperactivity disorder rating scale (ARS) [41, 42] ARS is based on DSM-IV criteria and parent or teacher report The ARS contains 18 items that include nine inattention

relatedness and nine hyperactivity and impulsivity

fac-tors Each item score ranges from 0 (never) to 3 (very

often) Therefore, the total range of score is 0 to 54 A

reasonable level of sensitivity, specificity and negative

predictive value for the diagnosis of ADHD is acquired

when the ARS total score is more than 14.5–15.5 [40] A

higher score indicates more severe problems [41]

Blood BDNF drawing

Blood samples were drawn from all participants at 2 pm

For the serum BDNF analysis, we used a serum separator

tube (SST) and allowed samples to clot for 30 min before

centrifugation for 15 min at approximately 1000×g The

serum was removed, and the separated serum layer was

aliquoted into 5-ml polypropylene cryo-vialsand stored

at −80  °C until assay analysis Plasma was collected on

ice using EDTA tubes and centrifuged for 15  min at

1000×g at 4 °C within 30 min of collection An additional

centrifugation step was conducted on the separated

plasma at 10,000×g for 10 min at 4 °C, as recommended

for complete platelet removal We removed the plasma,

and the separated plasma layer was aliquoted into 5-ml

polypropylene cryo-vials and stored at −80 °C until assay

analysis The samples were diluted with diluent included

in the R&D Human BDNF Quantikine ELISA kit

(Min-neapolis, Minnesota) to bring measured levels of BDNF

within the range of the standard provided The results are

reported in pg/ml

Statistical analyses

All statistical analyses were performed with SPSS

ver-sion 17.0 for windows The demographic variables (age,

maternal age at onset, birth weight, paternal, maternal

education, income, indirect smoking) and psychometric

properties (IQ, CCPT, CCTT, Stroop test, CBCL, ARS)

of the participants, were ascertained by descriptive

statis-tics Serum and plasma levels of BDNF were compared to

reference values A two-tailed Pearson χ2 test was used to

establish the level of correlation between the

psychomet-ric scores and serum and plasma BDNF levels Statistical

significance was reported for results above the 0.05 level

Results

Result of variables

Demographic data are shown in Table 1 A total of 28

children [13 boys (46 % of participants) and, 15 girls (54 %

of participants)] were recruited Most parents of the

participants had been educated for more than 12  years

(82.1 %) The psychometric properties of participants are

shown in Table 2 The mean full scale IQ of the

partici-pants was 106.89 ± 12.41 The mean CBCL scores were

as follows: internalizing problems (45.64 ± 10.31),

exter-nalizing problems (48.54 ± 7.34), total behavior problems

(46.68  ±  9.55), anxiety/depression (46.64  ±  9.83), and attention problems (43.86 ± 7.71) The mean ARS score was 6.04 ± 5.82 Serum or plasma BDNF levels did not differ statistically across the sexes or with age Addition-ally, there were no differences in psychometric scores across the sexes or with age, except for the CCPT com-mission error (visual) (p = 0.02) and ARS hyperactivity (p = 0.04), inattention (p = 0.005), total (p = 0.03) scores, which showed gender differences

Correlations with peripheral BDNF concentration and psychometric properties

We examined correlations with the Pearson χ2 test between the serum and plasma BDNF levels and the full scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) (Table 3) The serum BDNF level was negatively correlated with the FSIQ (r = −0.39, p = 0.04) and VIQ (r = −0.50, p = 0.01), but not with the PIQ (r = −0.12,

p = 0.56) (Table 3; Fig. 1) There was no significant rela-tionship between plasma BDNF level and each IQ scale Additionally, no correlation was found between the serum or plasma level of BDNF and the CCPT, ARS, CCTT or Stroop color-word test (Table 4) The total behavior problem and attention problem sections of the CBCL were positively related to plasma BDNF level [(r = 0.41, p = 0.03), (r = 0.44, p = 0.02)] (Table 5; Fig. 1)

No relationship was found between plasma BDNF and social withdrawal, somatic complaints, anxiety/depres-sion, social problems, Thought problems, delinquent behavior, aggressive behavior, internalizing or externaliz-ing problems on the CBCL No associations were found between serum BDNF level and any CBCL scores

Discussion

This study is the first to investigate the association between BDNF levels and preschool children’s cognitive development in healthy subjects We found that serum BDNF level was negatively associated with both full-scale and verbal IQ scores and that plasma BDNF level was negatively associated with CBCL attention and behavior problem scores

BDNF is an important factor in neuro-development [3 4] Our results show that BDNF may play a role in intelligence, attention and clinical symptoms of pre-school children with neuro-developmental disorders such as intellectual disability and ADHD Higher periph-eral BDNF concentration could be a biomarker of these states

There are some reports of an association between BDNF and intellectual disability and of a general inverse correlation with intelligence in children [23–25] Nel-son et al [23] reported elevated peripheral blood BDNF levels in neonates with intellectual disabilities than in

controls They suggested that BDNF dysregulation may

play a role in the development of intellectual

disabil-ity and that BDNF levels may be an early biomarker for

identification of intellectual disability [23] Miyazaki et al

[24] also found that children and adolescents (mean age:

11.0 ± 5.9 years), diagnosed with an intellectual

disabil-ity, had higher blood BDNF levels than controls They

concluded that elevated BDNF levels may reflect an

abnormal state in prenatal or early postnatal neuronal

development [24] However, Taurines et  al [25] found

no correlation between altered peripheral BDNF mRNA

expression and BDNF protein concentrations in blood of

children and adolescents with autism spectrum disorder

Research has been conducted on cognitive function

of BDNF over-expressed transgenic mice [10, 43] Croll

et  al [43] found that BDNF over-expressed transgenic

mice show significant impairment in learning (passive

avoidance) and increase locomotor activities (maze arm

entries) and hyper-excitability in the CA3 area of the

hip-pocampus They suggested that excess BDNF may

inter-fere with normal learning and memory, and this result

is due to too much excitability in the learning circuit or

too much plasticity leading to synaptic refinement [43] Cunha et  al [10] also described that overexpression of BDNF in the forebrain may reduce learning and memory formation in mice They proposed that the physiologi-cal amount of BDNF is helpful in learning and memory, but an increased or decreased level of BDNF induces inhibitory and excitatory neurotransmission in the brain, causing loss of synaptic refinement and impairment of learning and memory [5]

Some researchers found a relationship between a poly-morphism of the BDNF gene and cognitive functions in humans [44–46] Egan et al [44] reported that the Val-66Met polymorphism of the BDNF gene, valine (Val) to methionine (Met) substitution at codon 66, is related to poor episodic memory, abnormal hippocampal activa-tion, abnormal intracellular trafficking and dysregulation

of BDNF secretion in humans fMRI research of the Val-66Met polymorphism of the BDNF gene also described that the Val66Met polymorphism impacts memory related brain activity in the healthy humans Addition-ally, the Met allele of the BDNF Val66Met polymorphism

is related to increased serum BDNF levels in adults [46]

Table 1 Demographic variables of the participants

Paternal education (n, %)

Maternal education (n, %)

Income (n, %)

Indirect smoking

Serum BDNF level mean (SD) (pg/ml)

(8253.99)

(8582.34) Plasma BDNF level mean (SD) (pg/ml)

Therefore, we need additional research about single nucleotide polymorphisms of the BDNF gene in children with higher serum levels of BDNF such as those in this study

There are some controversial results about the relationship between BDNF and ADHD [20, 22,

47] Shim et  al [22] found that children (mean age: 8.8 ± 2.3 years), who are diagnosed with ADHD, have higher plasma BDNF levels than control children, and the severity of inattention problems have a positive

Table 2 Psychometric properties of the participants

* P < 0.05

a Direction in which a change in score indicates good function

IQ

Computerized continuous performance test

Visual (T score)

Auditory (T score)

CCTT (T score)

Stroop (T score)

CBCL score (T score)

ADHD rating scale

Table 3 Correlation coefficient of IQ with BDNF levels

a Direction in which a change in score indicates good function

Favorable

Pearson correlation coefficient

Pearson correlation coefficient

correlation with plasma BDNF levels They suggested

that increased BDNF levels possibly reflect a

compen-satory mechanism in the response of abnormal and

late brain maturation [22] However, Scassellati et  al

[47] found no difference in serum BDNF level between

ADHD children (mean age: 8.8 ± 2.3 years) and control

children Corominas-Roso et  al [20] reported that adults with ADHD (mean age: 33.43  ±  8.99  years) have lower BDNF levels than control adults They sug-gested that low BDNF levels may contribute to the neu-rodevelopmental deficit in ADHD [20] A study have reported that the serum BDNF level increases over the

Fig 1 Scatter plot of BDNF levels with FSIQ, VIQ, CBCL total problem behavior, and attention problem score

first several years and, then decreases after reaching

adult levels in humans [26] Therefore, more research

is needed on the association between peripheral BDNF

concentration and neuro developmental disorders in

human development

Animal studies have also reported controversial results

about the relationship of BDNF with inattention and

hyperactivity [43, 48–50] Young adult transgenic mice,

which over-express BDNF, have a tendency to spend

more time being mobile [43], but BDNF knockout adult

mice demonstrate more impulsive behavior, hyperactivity

and learning deficiency [48–50]

Some studies have reported on the association between the BDNF gene and ADHD [51–53] Of these studies, a cohort study on the association between the Val66Met polymorphism of BDNF and children with ADHD found that the Met allele is associated with ADHD symptoms, such as hyperactivity-impulsivity [53] Another study found that the Valine allele of the Val66Met polymor-phism of the BDNF gene is associated with the pathogen-esis of ADHD [52] Thus, additional studies are needed

on the association between peripheral BDNF concentra-tion and single nucleotide polymorphisms of the BDNF gene in children with ADHD

Table 4 Correlation coefficient of ADS, ARS, CCTT, and STROOP with BDNF levels

a Direction in which a change in score indicates good function

Pearson correlation

Computerized continuous performance test (T score)

CCTT (T score)

Stroop test (T score)

Table 5 Correlation coefficient of CBCL with BNDF levels

a Direction in which a change in score indicates good function

Pearson correlation

Our study used serum and plasma levels of BDNF to

investigate the relationships among peripheral blood

BDNF level and childhood IQ and neurobehavior In this

study, serum BDNF level was related to VIQ and FIQ

However, plasma BDNF was not associated with VIQ

and FIQ Plasma BDNF levels were related to

external-izing problems and attention problems according to the

CBCL, but not with serum BDNF levels Many other

studies have assessed the relationship between the serum

or plasma level of BDNF and neuropsychiatric or

devel-opmental disorders [16, 19, 20, 22, 24] However, there

is still no standard method to measure peripheral BDNF

levels Additionally, the relationship between serum and

plasma BDNF levels has not established Yoshimura et al

[54] reported that plasma and serum levels of BDNF

are positively correlated in healthy volunteers

How-ever, Bocchio-Chiavetto et  al [55] found no correlation

between plasma and serum levels of BDNF in major

depressive patients in a meta-analysis Some researchers

have suggested that plasma BDNF is a reliable indicator

of brain BDNF levels because of the little influence of the

BDNF that is stored in platelets [22, 56] Other

research-ers have suggested that serum BDNF is a valid marker

of brain BDNF because serum BDNF reflects the BDNF

accumulated by platelets during illness or treatment

peri-ods [57] Accordingly, we used two indicators, serum and

plasma BDNF Therefore, to use BDNF as a biomarker, a

standardized method of measurement of BDNF and the

source of peripheral BDNF is needed

This study has some limitations that must be

consid-ered First, we did not assess our subjects with structured

interviews to rule out psychiatric illnesses However, we

assessed their intelligence and psychiatric history using

a standardized intelligence scale and questionnaire

Sec-ond, we assessed the correlation between peripheral

blood BDNF and intelligence and psychiatric problems

in the same group Therefore, we could not compare the

absolute peripheral BDNF level of patients with ADHD

or other DSM-5 neurodevelopmental disorders Third,

this study was a cross-sectional study In BDNF

over-expressing mice, memory retention was impaired in

younger animals, but not in older ones [10] Thus, a

long-term follow up study on blood BDNF levels and

psycho-pathologies is needed Last, we included 28 preschool

children, and higher number of subjects would increase

statistical power

Conclusions

Our results suggest that high peripheral concentration of

BDNF is related to intelligence, inattention and

behavio-ral problems Further studies on BDNF metabolism are

required, using a standardized measurement method for

BDNF ascertainment, with parallel genetic analysis of

BDNF gene polymorphisms, with a robust sample size and with long-term follow-up are needed to further validate this line of research and to clarify the role and relevance

of differences in peripheral BDNF as a potential biomarker

Abbreviations

ADHD: attention‑deficit hyperactivity disorder; ARS: ADHD rating scale; BDNF: brain‑derived neurotrophic factor; CBCL: child behavior check list; CCPT: com‑ puterized continuous performance test; CCTT: children’s color trail test; FSIQ: full scale IQ; PIQ: performance IQ; STROOP: Stroop color‑word test; VIQ: verbal IQ; WISC: Wechsler Intelligence Scale for Children.

Authors’ contributions

SYB, SWC and YJP had full access to all the data in the study and take respon‑ sibility for the integrity of the data and the accuracy of the data analysis Study concept and design: SYB, SWC, YJP Acquisition, analysis, or interpretation of data: All authors Drafting of the manuscript: CWY, SYB Critical revision of the manuscript for important intellectual content: CWY, SYB Statistical analysis: SYB, SWC Obtained funding: SYB, SWC Administrative, technical, or material support: SYB, SWC Study supervision: SYB All authors critically revised the draft for important intellectual content, and subsequently read All authors read and approved the final manuscript.

Author details

1 Department of Psychiatry, Bugok National Hospital, Changnyeong‑gun, Gyeongsangnam‑do, South Korea 2 Department of Internal Medicine, Ulsan University Hospital, Ulsan, South Korea 3 Korea Institute on Behavioral Addic‑ tions, Easy Brain Clinic, Seoul, South Korea 4 Health Care and Information Research Institute, Namseoul University, Cheonan, South Korea 5 Department

of Psychiatry, Eulji University School of Medicine, Eulji General Hospital, 68 Hangeulbiseok‑Ro, Nowon‑Gu, Seoul 139‑711, South Korea

Acknowledgements

This work was supported entirely by the Biomedical Research Center Pro‑ motion Fund, Ulsan University Hospital The funding sources had no role in the design and conduct of the study.

Competing interests

The authors declare that they have no competing interests.

Received: 15 October 2015 Accepted: 22 April 2016

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